This invention relates to the use of dioxolenylmethyl carbamates which are useful in the production of neutral prodrugs from primary and secondary amines as well as the method of synthesis of such prodrugs. In particular, the novel prodrugs which are produced with a substituted 4-hydroxymethyl-2-oxo-1,3-dioxol-4-ene are presented.
The term "prodrug" denotes a derivative of a functional drug which derivative, when administered to a warm-blooded animal, "cleaves" in such a manner as to release the drug in its active form, at its target site or sites of activity. The enzymatic and/or chemical hydrolytic "cleavage" of the compound occurs in a manner such that the drug is released while the remaining "cleaved" promoiety remains non-toxic and is metabolized in such a manner that non-toxic, metabolic products are produced.
Pharmaceutically active compounds which are also known as drugs or pharmaceuticals or medicinals, which are amines or have an amine function therein can undergo protonation at physiological pH and are not always transported optimally through biological membranes in the body. For compounds which ionize, the rate of transport through biomembranes appears to be proportional to the concentration of undissociated molecules in solution and the lipid solubility.
It is often advantageous to perform derivatization of the polar amino groups to aid absorption, since this could make the compounds neutral, or more hydrophobic and hence more lipid soluble. Carbamylation confers such properties to amines since carbamates do not ionize at physiological pH. However, success with carbamate ester latentiation requires that it must be hydrolyzed to carbamic acid and the alcohol moiety after penetration through the biological barrier. This is especially true of carbamates of secondary amines, the rates of hydrolysis of which are 10.sup.5 to 10.sup.9 times slower than that of the corresponding primary amines. In this regard, there does not appear to be a carbamate ester specific hydrolytic enzyme in mammals. Though cholinesterase hydrolyze carbamates and become reversibly inhibited in the process, the rates are too slow for practical use. Hence, modified carbamates with an enzymically hydrolyzable ester function were designed as prodrugs for amines by Alexander (U.S. Pat. No. 4,760,057). Esterase catalyzed hydrolysis of the ester moiety triggers the regeneration of the parent amine from such derivatives as depicted below. ##STR1##
In the acyloxyalkyl carbamates described above, the acetal ester portion of the molecule is often derived from formaldehyde which is undesirable or from acetaldehyde. Use of the latter results in the introduction of a new chiral center, which .may be useful or problematic. Application of the above invention to amino drugs which carry additional asymmetric centers elsewhere in the structure can result in the formation of a pair of diasteric isomeric prodrugs. The hydrolytic susceptibility of these diastereoisomers could be different and hence they could hydrolyze at widely different rates to regenerate the parent drug. Therefore, there is a need for a prodrug strategy that would confer bioreversibility and neutrality to the prodrug at physiological pH and at the same time would not introduce additional chiral centers in the prodrug, or generate undesirable side products.
2-Oxo-1,3-dioxolenylmethyl esters of carboxylic acid with the structure below, have been used as prodrugs for a variety of carboxyl-containing drugs. (Miyauchi, et al., Chem. Pharm. Bull. 1990, 38, 1077-1078; Saari, et al., J. Med. Chem., 1984, 27, 713-717.) ##STR2## where R is a drug containing a carboxylic acid group.
5-Alkyl-2-oxo-1,3-dioxol-4-ylmethyl esters have been extensively investigated as prodrugs for carboxylic acid groups on B-lactam antibiotics of the penicillin, cephalosporin and thienamycin class of drugs. Lenampicillin (Ikeda, et al., J. Antibiotics, 1984, 32, 4316) is an orally active ampicillin prodrug using this prodrug group.
The 2-oxo-1,3-dioxolenylmethyl group has also been used as a prodrug moiety on the amino group of amino functional drugs as shown below (Sakamoto, et al., Chem. Pharm. Bull., 1985, 33, 4870-4877. ) ##STR3## where R.sup.1 R.sup.2 N is a drag containing an amino group. It has been used to alkylate the piperazino nitrogen in norfloxacin (Sakamoto, et al, Chem. Pharm. Bull., 1985, 33, 4870). The alkylated nofloxacin regenerated the parent drug on oral administration to rats.
The direct alkylation of the amino group with the oxodioxolenylmethyl functionality as above gives a substituted amine that can undergo protonation and is still ionizable. That is, the hydrophilic nature of the amino group or solubility property of the prodrug is not significantly changed by this type of modification.
U.S. Pat. No. 4,760,057, discloses alkalylated compounds prepared by a two-step process comprising the steps of treating a primary or secondary amine with an alpha -haloalkyl halo-formate to give an alpha -haloalkyl carbamate followed by displacement of the halogen with an acyloxy group by treatment with a metal salt of the carboxylic acid; the metal used could be alkali, alkaline earth, or silver, mercury, and the like.
However, there are instances where the application of the method could result in poor yields as a result of side reactions. For example, silver salts could interact with a free thiol function or mercury salts could give rise to mercuration of highly activated aromatic rings and double bonds. Therefore, there exists a need for a prodrug forming mechanism that will result in primary or secondary amines which are less susceptible to ionization at physiological pH and are free from the side reactions already discussed.
Accordingly, this invention provides novel dioxolenyl-methyl carbonate derivatives which are useful as starting materials for novel one-step synthesis of bioreversible prodrug moieties for drugs or medicaments having primary or secondary amine functions thereon which when administered to warm-blooded animals are characterized as being more readily bioavailable, less irritating to topical and gastric mucosal membranes and more permeable through topical membranes, e.g., ophthalmic membrane or skin, than are the parent drugs from which they are derived.
The prodrug of this invention form from conventional primary and secondary amine compounds which, following administration, will "cleave" in such a manner as to enable the original parent moiety to be released at its therapeutic site or sites of activity and to further permit the cleaved moiety, unassociated with the parent moiety, to be metabolized in a non-toxic fashion.
This invention also provides prodrugs of medicaments or drugs having primary or secondary amine functions thereon to provide increased biomembrane transport such that the drug is more bioavailable from the GI tract, the rectum, the skin and the eye of the human body.
A further advantage of this invention is to provide prodrug compounds which utilize hydrolytic enzymes to generate the parent amine-type drug from the prodrug or carbamate protecting group. An additional advantage of this invention is that it provides prodrugs of amines wherein the reactive function is remote from the carbamate carbonyl and thus enzymatic hydrolysis leads to the generation of carbamic acid which will undergo fast decarboxylation releasing the amine parent drug.
In the instant invention, the problems observed with the previously reported systems have been overcome. In the instant invention, a primary or secondary amino functional drug is convened to produce the prodrug moiety shown below: ##STR4## An oxodoxolenyl methyl carbamate prodrug results by carbamylation of the amino group with a substituted 4-hydroxymethyl-2-oxo-1,3-dioxol-4-ene to produce the prodrug moiety.
Carbamylation of the amino group provides the following advantages for the resulting prodrug:
(a) carbamylated amines do not ionize and hence are more compatible with organic and lipoidal systems; PA0 (b) the modification is applicable to primary and secondary amines essentially irrespective of basicity; PA0 (c) there is potential for chemical selectivity in the presence of competing functionalities such as hydroxyl; PA0 (d) they are chemically stable; PA0 (e) when R.sup.3 and R.sup.4 are the same, this promoiety produces a prodrug with no additional chiral centers; and PA0 (f) enzyme catalyzed ring opening of the oxodioxolene ring triggers the regeneration of the parent primary or secondary amine as shown below: ##STR5## PA0 R.sup.3 is hydrogen, straight or branched chain C.sub.1 to C.sub.6 alkyl, straight or branched chain C.sub.1 to C.sub.6 alkenyl, phenyl, substituted phenyl wherein the substitutents are fluoro, chloro, bromo, iodo, nitro, C1 to C6 carboxyalkyl, or C1 to C6 alkyloxy; PA0 R4 is hydrogen, straight or branchanged chain C.sub.1 to C.sub.6 alkyl, straight or branched chain C.sub.1 to C.sub.6 alkenyl, phenyl, substituted phenyl wherein the substitutents are fluoro, chloro, bromo, iodo, nitro, C1 to C6 carboxyalkyl, or C1 to C6 alkyloxy; PA0 R5 is hydrogen, straight or branchanged chain C.sub.1 to C.sub.6 alkyl, straight or branched chain C.sub.1 to C.sub.6 alkenyl, phenyl, substituted phenyl wherein the substitutents are fluoro, chloro, bromo, iodo, nitro, C1 to C6 carboxyalkyl, or C1 to C6 alkyloxy.
The novel method of this invention provides for the production of a bioreversible prodrug from primary or secondary amines wherein the ionizability of the resultant prodrug, under physiologic pH, is masked such that lipid solubility is increased, and hydrophilic properties are reduced. Further, the novel process of this invention, results in high yield of the prodrug without the use of reagents that promote side reactions.